Paediatrics (RCH) - Research Publications

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    Kidney organoids: accurate models or fortunate accidents
    Little, MH ; Combes, AN (COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2019-10-01)
    There are now many reports of human kidney organoids generated via the directed differentiation of human pluripotent stem cells (PSCs) based on an existing understanding of mammalian kidney organogenesis. Such kidney organoids potentially represent tractable tools for the study of normal human development and disease with improvements in scale, structure, and functional maturation potentially providing future options for renal regeneration. The utility of such organotypic models, however, will ultimately be determined by their developmental accuracy. While initially inferred from mouse models, recent transcriptional analyses of human fetal kidney have provided greater insight into nephrogenesis. In this review, we discuss how well human kidney organoids model the human fetal kidney and how the remaining differences challenge their utility.
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    Ferrodraco lentoni gen. et sp. nov., a new ornithocheirid pterosaur from the Winton Formation (Cenomanian-lower Turonian) of Queensland, Australia.
    Pentland, AH ; Poropat, SF ; Tischler, TR ; Sloan, T ; Elliott, RA ; Elliott, HA ; Elliott, JA ; Elliott, DA (Springer Science and Business Media LLC, 2019-10-03)
    The Australian pterosaur record is poor by world standards, comprising fewer than 20 fragmentary specimens. Herein, we describe the new genus and species Ferrodraco lentoni gen. et sp. nov., based on the most complete pterosaur specimen ever found in Australia, and the first reported from the Winton Formation (Cenomanian-lower Turonian). The presence of premaxillary and mandibular crests, and spike-shaped teeth with subcircular bases, enable Ferrodraco to be referred to Anhangueria. Ferrodraco can be distinguished from all other anhanguerian pterosaurs based on two dental characters: the first premaxillary and mandibular tooth pairs are small; and the fourth-seventh tooth pairs are smaller than the third and eighth ones. Ferrodraco was included in a phylogenetic analysis of Pterosauria and resolved as the sister taxon to Mythunga camara (upper Albian Toolebuc Formation, Australia), with that clade occupying the most derived position within Ornithocheiridae. Ornithocheirus simus (Albian Cambridge Greensand, England), Coloborhynchus clavirostris (Valanginian Hastings Sands, England), and Tropeognathus mesembrinus (upper Aptian-lower Albian Romualdo Formation, Brazil) were resolved as successive sister taxa, which suggests that ornithocheirids were cosmopolitan during the Albian-Cenomanian. Furthermore, the stratigraphic age of Ferrodraco lentoni (Cenomanian-lower Turonian) implies that anhanguerians might have survived later in Australia than elsewhere.
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    Efficacy of mass drug administration with ivermectin for control of scabies and impetigo, with coadministration of azithromycin: a single-arm community intervention trial
    Romani, L ; Marks, M ; Sokana, O ; Nasi, T ; Kamoriki, B ; Cordell, B ; Wand, H ; Whitfeld, MJ ; Engelman, D ; Solomon, AW ; Kaldor, JM ; Steer, AC (ELSEVIER SCI LTD, 2019-05)
    BACKGROUND: In small community-based trials, mass drug administration of ivermectin has been shown to substantially decrease the prevalence of both scabies and secondary impetigo; however, their effect at large scale is untested. Additionally, combined mass administration of drugs for two or more neglected diseases has potential practical advantages, but efficacy of potential combinations should be confirmed. METHODS: The azithromycin ivermectin mass drug administration (AIM) trial was a prospective, single-arm, before-and-after, community intervention study to assess the efficacy of mass drug administration of ivermectin for scabies and impetigo, with coadministration of azithromycin for trachoma. Mass drug administration was offered to the entire population of Choiseul Province, Solomon Islands, and of this population we randomly selected two sets of ten sentinel villages for monitoring, one at baseline and the other at 12 months. Participants were offered a single dose of 20 mg/kg azithromycin, using weight-based bands. Children weighing less than 12·5 kg received azithromycin oral suspension (20 mg/kg), and infants younger than 6 months received topical 1% tetracycline ointment. For ivermectin, participants were offered two doses of oral ivermectin 200 μg/kg 7-14 days apart using weight-based bands, or 5% permethrin cream 7-14 days apart if ivermectin was contraindicated. Our study had the primary outcomes of safety and feasibility of large-scale mass coadministration of oral ivermectin and azithromycin, which have been previously reported. We report here the prevalence of scabies and impetigo in residents of the ten baseline villages compared with those in the ten 12-month villages, as measured by examination of the skin, which was a secondary outcome of the trial. Further outcomes were comparison of the number of all-cause outpatient attendances at government clinics in Choiseul Province at various timepoints before and after mass drug administration. The trial was registered with the Australian and New Zealand Trials Registry (ACTRN12615001199505). FINDINGS: During September, 2015, over 4 weeks, 26 188 people (99·3% of the estimated population of Choiseul [n=26 372] as determined at the 2009 census) were treated. At baseline, 1399 (84·2%) of 1662 people living in the first ten villages had their skin examined, of whom 261 (18·7%) had scabies and 347 (24·8%) had impetigo. At 12 months after mass drug administration, 1261 (77·6%) of 1625 people in the second set of ten villages had their skin examined, of whom 29 (2·3%) had scabies (relative reduction 88%, 95% CI 76·5-99·3) and 81 (6·4%) had impetigo (relative reduction 74%, 63·4-84·7). In the 3 months after mass drug administration, 10 614 attended outpatient clinics for any reason compared with 16 602 in the 3 months before administration (decrease of 36·1%, 95% CI 34·7-37·6), and during this period attendance for skin sores, boils, and abscesses decreased by 50·9% (95% CI 48·6-53·1). INTERPRETATION: Ivermectin-based mass drug administration can be scaled to a population of over 25 000 with high efficacy and this level of efficacy can be achieved when mass drug administration for scabies is integrated with mass drug administration of azithromycin for trachoma. These findings will contribute to development of population-level control strategies. Further research is needed to assess durability and scalability of mass drug administration in larger, non-island populations, and to assess its effect on the severe bacterial complications of scabies. FUNDING: International Trachoma Initiative, Murdoch Children's Research Institute, Scobie and Claire Mackinnon Trust, and the Wellcome Trust.
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    Immunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial
    Temple, B ; Nguyen, TT ; Vo, TTD ; Bright, K ; Licciardi, PV ; Marimla, RA ; Nguyen, CD ; Uyen, DY ; Balloch, A ; Tran, NH ; Mulholland, EK (ELSEVIER SCI LTD, 2019-05)
    BACKGROUND: Few data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13. METHODS: In this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3 + 1 (group A), 3 + 0 (group B), 2 + 1 (group C), or two-dose schedule (group D); PCV13 in a 2 + 1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 μg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov, number NCT01953510. FINDINGS: Of 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 μg/mL did not differ between groups at the 10% level for any serotype (PCV10-PCV13 risk difference -2·1% [95% CI -4·8 to -0·1] for serotype 1; -1·3% [-3·7 to 0·6] for serotype 4; -3·4% [-6·8 to -0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; -1·3% [-3·7 to 0·6] for serotype 7F; -1·6% [-5·1 to 1·7] for serotype 9V; 0·0% [-2·7 to 2·9] for serotype 14; -2·1% [-5·3 to 0·9] for serotype 18C; 0·0% [-2·2 to 2·3] for serotype 19F; and -11·6% [-18·2 to -4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reactogenicity and serious adverse events were monitored according to good clinical practice guidelines, and the profiles were similar in the two groups. INTERPRETATION: PCV10 and PCV13 are similarly highly immunogenic when used in 2 + 1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings. FUNDING: National Health and Medical Research Council of Australia, and Bill & Melinda Gates Foundation.
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    Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016
    Johnson, CO ; Minh, N ; Roth, GA ; Nichols, E ; Alam, T ; Abate, D ; Abd-Allah, F ; Abdelalim, A ; Abraha, HN ; Abu-Rmeileh, NM ; Adebayo, OM ; Adeoye, AM ; Agarwal, G ; Agrawal, S ; Aichour, AN ; Aichour, I ; Aichour, MTE ; Alahdab, F ; Ali, R ; Alvis-Guzman, N ; Anber, NH ; Anjomshoa, M ; Arabloo, J ; Arauz, A ; Arnlov, J ; Arora, A ; Awasthi, A ; Banach, M ; Barboza, MA ; Barker-Collo, SL ; Barnighausen, TW ; Basu, S ; Belachew, AB ; Belayneh, YM ; Bennett, DA ; Bensenor, IM ; Bhattacharyya, K ; Biadgo, B ; Bijani, A ; Bikbov, B ; Bin Sayeed, MS ; Butt, ZA ; Cahuana-Hurtado, L ; Carrero, JJ ; Carvalho, F ; Castaneda-Orjuela, CA ; Castro, F ; Catala-Lopez, F ; Chaiah, Y ; Chiang, PP-C ; Choi, J-YJ ; Christensen, H ; Chu, D-T ; Cortinovis, M ; Moura Damasceno, AA ; Dandona, L ; Dandona, R ; Daryani, A ; Davletov, K ; De Courten, B ; De la Cruz-Gongora, V ; Degefa, MG ; Dharmaratne, SD ; Diaz, D ; Dubey, M ; Duken, EE ; Edessa, D ; Endres, M ; Faraon, EJA ; Farzadfar, F ; Fernandes, E ; Fischer, F ; Flor, LS ; Ganji, M ; Gebre, AK ; Gebremichael, TG ; Geta, B ; Gezae, KE ; Gill, PS ; Gnedovskaya, EV ; Gomez-Dantes, H ; Goulart, AC ; Grosso, G ; Guo, Y ; Gupta, R ; Haj-Mirzaian, A ; Haj-Mirzaian, A ; Hamidi, S ; Hankey, GJ ; Hassen, HY ; Hay, SI ; Hegazy, MI ; Heidari, B ; Herial, NA ; Hosseini, MA ; Hostiuc, S ; Irvani, SSN ; Islam, SMS ; Jahanmehr, N ; Javanbakht, M ; Jha, RP ; Jonas, JB ; Jozwiak, JJ ; Jurisson, M ; Kahsay, A ; Kalani, R ; Kalkonde, Y ; Kamil, TA ; Kanchan, T ; Karch, A ; Karimi, N ; Karimi-Sari, H ; Kasaeian, A ; Kassa, TD ; Kazemeini, H ; Kefale, AT ; Khader, YS ; Khalil, IA ; Khan, EA ; Khang, Y-H ; Khubchandani, J ; Kim, D ; Kim, YJ ; Kisa, A ; Kivimaki, M ; Koyanagi, A ; Krishnamurthi, RK ; Kumar, GA ; Lafranconi, A ; Lewington, S ; Li, S ; Lo, WD ; Lopez, AD ; Lorkowski, S ; Lotufo, PA ; Mackay, MT ; Majdan, M ; Majdzadeh, R ; Majeed, A ; Malekzadeh, R ; Manafi, N ; Mansournia, MA ; Mehndiratta, MM ; Mehta, V ; Mengistu, G ; Meretoja, A ; Meretoja, TJ ; Miazgowski, B ; Miazgowski, T ; Miller, TR ; Mirrakhimov, EM ; Mohajer, B ; Mohammad, Y ; Mohammadoo-Khorasani, M ; Mohammed, S ; Mohebi, F ; Mokdad, AH ; Mokhayeri, Y ; Moradi, G ; Morawska, L ; Velasquez, IM ; Mousavi, SM ; Muhammed, OSS ; Muruet, W ; Naderi, M ; Naghavi, M ; Naik, G ; Nascimento, BR ; Negoi, RI ; Cuong, TN ; Long, HN ; Nirayo, YL ; Norrving, B ; Noubiap, JJ ; Ofori-Asenso, R ; Ogbo, FA ; Olagunju, AT ; Olagunju, TO ; Owolabi, MO ; Pandian, JD ; Patel, S ; Perico, N ; Piradov, MA ; Polinder, S ; Postma, MJ ; Poustchi, H ; Prakash, V ; Qorbani, M ; Rafiei, A ; Rahim, F ; Rahimi, K ; Rahimi-Movaghar, V ; Rahman, M ; Rahman, MA ; Reis, C ; Remuzzi, G ; Renzaho, AMN ; Ricci, S ; Roberts, NLS ; Robinson, SR ; Roever, L ; Roshandel, G ; Sabbagh, P ; Safari, H ; Safari, S ; Safiri, S ; Sahebkar, A ; Zahabi, SS ; Samy, AM ; Santalucia, P ; Santos, IS ; Santos, JV ; Milicevic, MMS ; Sartorius, B ; Sawant, AR ; Schutte, AE ; Sepanlou, SG ; Shafieesabet, A ; Shaikh, MA ; Shams-Beyranvand, M ; Sheikh, A ; Sheth, KN ; Shibuya, K ; Shigematsu, M ; Shin, M-J ; Shiue, I ; Siabani, S ; Sobaih, BH ; Sposato, LA ; Sutradhar, I ; Sylaja, PA ; Szoeke, CEI ; Ao, BJT ; Temsah, M-H ; Temsah, O ; Thrift, AG ; Tonelli, M ; Topor-Madry, R ; Bach, XT ; Khanh, BT ; Truelsen, TC ; Tsadik, AG ; Ullah, I ; Uthman, OA ; Vaduganathan, M ; Valdez, PR ; Vasankari, TJ ; Vasanthan, R ; Venketasubramanian, N ; Vosoughi, K ; Giang, TV ; Waheed, Y ; Weiderpass, E ; Weldegwergs, KG ; Westerman, R ; Wolfe, CDA ; Wondafrash, DZ ; Xu, G ; Yadollahpour, A ; Yamada, T ; Yatsuya, H ; Yimer, EM ; Yonemoto, N ; Yousefifard, M ; Yu, C ; Zaidi, Z ; Zamani, M ; Zarghi, A ; Zhang, Y ; Zodpey, S ; Feigin, VL ; Vos, T ; Murray, CJL (ELSEVIER SCIENCE INC, 2019-05)
    BACKGROUND: Stroke is a leading cause of mortality and disability worldwide and the economic costs of treatment and post-stroke care are substantial. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic, comparable method of quantifying health loss by disease, age, sex, year, and location to provide information to health systems and policy makers on more than 300 causes of disease and injury, including stroke. The results presented here are the estimates of burden due to overall stroke and ischaemic and haemorrhagic stroke from GBD 2016. METHODS: We report estimates and corresponding uncertainty intervals (UIs), from 1990 to 2016, for incidence, prevalence, deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs). DALYs were generated by summing YLLs and YLDs. Cause-specific mortality was estimated using an ensemble modelling process with vital registration and verbal autopsy data as inputs. Non-fatal estimates were generated using Bayesian meta-regression incorporating data from registries, scientific literature, administrative records, and surveys. The Socio-demographic Index (SDI), a summary indicator generated using educational attainment, lagged distributed income, and total fertility rate, was used to group countries into quintiles. FINDINGS: In 2016, there were 5·5 million (95% UI 5·3 to 5·7) deaths and 116·4 million (111·4 to 121·4) DALYs due to stroke. The global age-standardised mortality rate decreased by 36·2% (-39·3 to -33·6) from 1990 to 2016, with decreases in all SDI quintiles. Over the same period, the global age-standardised DALY rate declined by 34·2% (-37·2 to -31·5), also with decreases in all SDI quintiles. There were 13·7 million (12·7 to 14·7) new stroke cases in 2016. Global age-standardised incidence declined by 8·1% (-10·7 to -5·5) from 1990 to 2016 and decreased in all SDI quintiles except the middle SDI group. There were 80·1 million (74·1 to 86·3) prevalent cases of stroke globally in 2016; 41·1 million (38·0 to 44·3) in women and 39·0 million (36·1 to 42·1) in men. INTERPRETATION: Although age-standardised mortality rates have decreased sharply from 1990 to 2016, the decrease in age-standardised incidence has been less steep, indicating that the burden of stroke is likely to remain high. Planned updates to future GBD iterations include generating separate estimates for subarachnoid haemorrhage and intracerebral haemorrhage, generating estimates of transient ischaemic attack, and including atrial fibrillation as a risk factor. FUNDING: Bill & Melinda Gates Foundation.
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    ADPedKD: A Global Online Platform on the Management of Children With ADPKD
    De Rechter, S ; Bockenhauer, D ; Guay-Woodford, LM ; Liu, I ; Mallett, AJ ; Soliman, NA ; Sylvestre, LC ; Schaefer, F ; Liebau, MC ; Mekahli, D ; Adamczyk, P ; Akinci, N ; Alpay, H ; Ardelean, C ; Ayasreh, N ; Aydin, Z ; Bael, A ; Baudouin, V ; Bayrakci, US ; Bensman, A ; Bialkevich, H ; Biebuyck, A ; Boyer, O ; Bjanid, O ; Brylka, A ; Caliskan, S ; Cambier, A ; Camelio, A ; Carbone, V ; Charbit, M ; Chiodini, B ; Chirita, A ; Cicek, N ; Cerkauskiene, R ; Collard, L ; Conceicao, M ; Constantinescu, I ; Couderc, A ; Crapella, B ; Cvetkovic, M ; Dima, B ; Diomeda, F ; Docx, M ; Dolan, N ; Dossier, C ; Drozdz, D ; Drube, J ; Dunand, O ; Dusan, P ; Eid, LA ; Emma, F ; Espino Hernandez, M ; Fila, M ; Furlano, M ; Gafencu, M ; Ghuysen, M ; Giani, M ; Giordano, M ; Girisgen, I ; Godefroid, N ; Godron-Dubrasquet, A ; Gojkovic, I ; Gonzalez, E ; Gokce, I ; Groothoff, JW ; Guarino, S ; Guffens, A ; Hansen, P ; Harambat, J ; Haumann, S ; He, G ; Heidet, L ; Helmy, R ; Hemery, F ; Hooman, N ; Ilanas, B ; Jankauskiene, A ; Janssens, P ; Karamaria, S ; Kazyra, I ; Koenig, J ; Krid, S ; Krug, P ; Kwon, V ; La Manna, A ; Leroy, V ; Litwin, M ; Lombet, J ; Longo, G ; Lungu, AC ; Mallawaarachchi, A ; Marin, A ; Marzuillo, P ; Massella, L ; Mastrangelo, A ; McCarthy, H ; Miklaszewska, M ; Moczulska, A ; Montini, G ; Morawiec-Knysak, A ; Morin, D ; Murer, L ; Negru, I ; Nobili, F ; Obrycki, L ; Otoukesh, H ; Ozcan, S ; Pape, L ; Papizh, S ; Parvex, P ; Pawlak-Bratkowska, M ; Prikhodina, L ; Prytula, A ; Quinlan, C ; Raes, A ; Ranchin, B ; Ranguelov, N ; Repeckiene, R ; Ronit, C ; Salomon, R ; Santagelo, R ; Saygili, SK ; Schaefer, S ; Schreuder, M ; Schurmans, T ; Seeman, T ; Segers, N ; Sinha, M ; Snauwaert, E ; Spasojevic, B ; Stabouli, S ; Stoica, C ; Stroescu, R ; Szczepanik, E ; Szczepanska, M ; Taranta-Janusz, K ; Teixeira, A ; Thumfart, J ; Tkaczyk, M ; Torra, R ; Torres, D ; Tram, N ; Utsch, B ; Vande Walle, J ; Vieux, R ; Vitkevic, R ; Wilhelm-Bals, A ; Wuehl, E ; Yildirim, ZY ; Yuksel, S ; Zachwieja, K (ELSEVIER SCIENCE INC, 2019-09)
    BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of renal failure. For several decades, ADPKD was regarded as an adult-onset disease. In the past decade, it has become more widely appreciated that the disease course begins in childhood. However, evidence-based guidelines on how to manage and approach children diagnosed with or at risk of ADPKD are lacking. Also, scoring systems to stratify patients into risk categories have been established only for adults. Overall, there are insufficient data on the clinical course during childhood. We therefore initiated the global ADPedKD project to establish a large international pediatric ADPKD cohort for deep characterization. METHODS: Global ADPedKD is an international multicenter observational study focusing on childhood-diagnosed ADPKD. This collaborative project is based on interoperable Web-based databases, comprising 7 regional and independent but uniformly organized chapters, namely Africa, Asia, Australia, Europe, North America, South America, and the United Kingdom. In the database, a detailed basic data questionnaire, including genetics, is used in combination with data entry from follow-up visits, to provide both retrospective and prospective longitudinal data on clinical, radiologic, and laboratory findings, as well as therapeutic interventions. DISCUSSION: The global ADPedKD initiative aims to characterize in detail the most extensive international pediatric ADPKD cohort reported to date, providing evidence for the development of unified diagnostic, follow-up, and treatment recommendations regarding modifiable disease factors. Moreover, this registry will serve as a platform for the development of clinical and/or biochemical markers predicting the risk of early and progressive disease.
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    Safety and efficacy of herbal medicine for acute intracerebral hemorrhage (CRRICH): a multicentre randomised controlled trial
    Zeng, L ; Tang, G ; Wang, J ; Zhong, J ; Xia, Z ; Li, J ; Chen, G ; Zhang, Y ; Luo, S ; Huang, G ; Zhao, Q ; Wan, Y ; Chen, C ; Zhu, K ; Qiao, H ; Wang, J ; Huang, T ; Liu, X ; Zhang, Q ; Lin, R ; Li, H ; Gong, B ; Chen, X ; Zhou, Y ; Wen, Z ; Guo, J (BMJ PUBLISHING GROUP, 2019-05)
    OBJECTIVE: To evaluate the safety and efficacy of removing blood stasis (RBS) herbal medicine for the treatment of acute intracerebral haemorrhage (AICH) within a 6-hour time window. STUDY DESIGN: A randomised, multicentre, double-blind, placebo-controlled study performed in 14 hospitals in China. PARTICIPANTS AND INTERVENTIONS: Patients with AICH were randomly assigned to receive a placebo, the ICH-1 (Intracerebral Haemorrhage) formula (eight herbs, including the RBS herbs hirudo and tabanus) or the ICH-2 formula (six herbs without the RBS herbs hirudo and tabanus) within 6 hours of ICH onset. OUTCOMES: The primary safety outcome was the incidence of haematoma enlargement at 24 hours and at 10 days after treatment. The secondary outcome was the incidence of poor prognosis (mortality or modified Rankin Scale score ≥5) assessed at 90 days after symptom onset. RESULTS: A total of 324 subjects were randomised between October 2013 and May 2016: 105 patients received placebo; 108 patients received the ICH-1 formula; and 111 patients received the ICH-2 formula. The incidence of haematoma enlargement at 24 hours was 7.8% in the placebo group, 12.3% in the ICH-1 group and 7.5% in the ICH-2 group; the incidence of haematoma enlargement on day 10 was 1.1% in the placebo group, 1.1% in the ICH-1 group, and 3.1% in the ICH-2 group, with no significant differences among the groups (P>0.05). The mortality rates were 3.8% in the placebo group, 2.8% in the ICH-1 group, and 0.9% in the ICH-2 group; the incidences of poor prognosis were 7.1% in the placebo group, 6.0% in the ICH-1 group and 4.8% in the ICH-2 group at 3 months, with no significant differences among the groups (p>0.05). However, the overall frequency of treatment-emergent adverse events in the ICH-1 group (12.1%) was higher among the three groups (5.8% and 2.8%, respectively, p<0.05). All three cases of serious adverse events were in the ICH-1 group. CONCLUSIONS: Ultra-early administration of ICH-1 formula for AICH patients did not exert significant beneficial effects on clinical outcomes but increased the risk of bleeding, which probably resulted from the inclusion of RBS herbal medicines in ICH-1. TRIALREGISTRATION NUMBER: NCT01918722.
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    Heavy menstrual bleeding among women aged 18-50years living in Beijing, China: prevalence, risk factors, and impact on daily life
    Ding, C ; Wang, J ; Cao, Y ; Pan, Y ; Lu, X ; Wang, W ; Zhuo, L ; Tian, Q ; Zhan, S (BMC, 2019-02-04)
    BACKGROUND: Heavy menstrual bleeding (HMB) has been shown to have a profound negative impact on women's quality of life and lead to increases in health care costs; however, data on HMB among Chinese population is still rather limited. The present study therefore aimed to determine the current prevalence and risk factors of subjectively experienced HMB in a community sample of Chinese reproductive-age women, and to evaluate its effect on daily life. METHODS: We conducted a questionnaire survey in 2356 women aged 18-50 years living in Beijing, China, from October 2014-July 2015. A multivariate logistic regression model was used to identify risk factors for HMB. RESULTS: Overall, 429 women experienced HMB, giving a prevalence of 18.2%. Risk factors associated with HMB included uterine fibroids (adjusted odds ratio [OR] =2.12, 95% confidence interval [CI] = 1.42-3.16, P < 0.001) and multiple abortions (≥3) (adjusted OR = 3.44, 95% CI = 1.82-6.49, P < 0.001). Moreover, women in the younger age groups (≤24 and 25-29 years) showed higher risks for HMB, and those who drink regularly were more likely to report heavy periods compared with never drinkers (adjusted OR = 2.78, 95% CI = 1.20-6.46, P = 0.017). In general, women experiencing HMB felt more practical discomforts and limited life activities while only 81 (18.9%) of them had sought health care for their heavy bleeding. CONCLUSIONS: HMB was highly prevalent among Chinese women and those reporting heavy periods suffered from greater menstrual interference with daily lives. More information and health education programs are urgently needed to raise awareness of the consequences of HMB, encourage women to seek medical assistance and thus improve their quality of life.
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    Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation.
    Gurumurthy, CB ; O'Brien, AR ; Quadros, RM ; Adams, J ; Alcaide, P ; Ayabe, S ; Ballard, J ; Batra, SK ; Beauchamp, M-C ; Becker, KA ; Bernas, G ; Brough, D ; Carrillo-Salinas, F ; Chan, W ; Chen, H ; Dawson, R ; DeMambro, V ; D'Hont, J ; Dibb, KM ; Eudy, JD ; Gan, L ; Gao, J ; Gonzales, A ; Guntur, AR ; Guo, H ; Harms, DW ; Harrington, A ; Hentges, KE ; Humphreys, N ; Imai, S ; Ishii, H ; Iwama, M ; Jonasch, E ; Karolak, M ; Keavney, B ; Khin, N-C ; Konno, M ; Kotani, Y ; Kunihiro, Y ; Lakshmanan, I ; Larochelle, C ; Lawrence, CB ; Li, L ; Lindner, V ; Liu, X-D ; Lopez-Castejon, G ; Loudon, A ; Lowe, J ; Jerome-Majewska, LA ; Matsusaka, T ; Miura, H ; Miyasaka, Y ; Morpurgo, B ; Motyl, K ; Nabeshima, Y-I ; Nakade, K ; Nakashiba, T ; Nakashima, K ; Obata, Y ; Ogiwara, S ; Ouellet, M ; Oxburgh, L ; Piltz, S ; Pinz, I ; Ponnusamy, MP ; Ray, D ; Redder, RJ ; Rosen, CJ ; Ross, N ; Ruhe, MT ; Ryzhova, L ; Salvador, AM ; Alam, SS ; Sedlacek, R ; Sharma, K ; Smith, C ; Staes, K ; Starrs, L ; Sugiyama, F ; Takahashi, S ; Tanaka, T ; Trafford, AW ; Uno, Y ; Vanhoutte, L ; Vanrockeghem, F ; Willis, BJ ; Wright, CS ; Yamauchi, Y ; Yi, X ; Yoshimi, K ; Zhang, X ; Zhang, Y ; Ohtsuka, M ; Das, S ; Garry, DJ ; Hochepied, T ; Thomas, P ; Parker-Thornburg, J ; Adamson, AD ; Yoshiki, A ; Schmouth, J-F ; Golovko, A ; Thompson, WR ; Lloyd, KCK ; Wood, JA ; Cowan, M ; Mashimo, T ; Mizuno, S ; Zhu, H ; Kasparek, P ; Liaw, L ; Miano, JM ; Burgio, G (Springer Science and Business Media LLC, 2019-08-26)
    BACKGROUND: CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up to 16% efficiency in generating conditional knockout (cKO or floxed) alleles by microinjection of 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides as donors (referred herein as "two-donor floxing" method). RESULTS: We re-evaluate the two-donor method from a consortium of 20 laboratories across the world. The dataset constitutes 56 genetic loci, 17,887 zygotes, and 1718 live-born mice, of which only 15 (0.87%) mice contain cKO alleles. We subject the dataset to statistical analyses and a machine learning algorithm, which reveals that none of the factors analyzed was predictive for the success of this method. We test some of the newer methods that use one-donor DNA on 18 loci for which the two-donor approach failed to produce cKO alleles. We find that the one-donor methods are 10- to 20-fold more efficient than the two-donor approach. CONCLUSION: We propose that the two-donor method lacks efficiency because it relies on two simultaneous recombination events in cis, an outcome that is dwarfed by pervasive accompanying undesired editing events. The methods that use one-donor DNA are fairly efficient as they rely on only one recombination event, and the probability of correct insertion of the donor cassette without unanticipated mutational events is much higher. Therefore, one-donor methods offer higher efficiencies for the routine generation of cKO animal models.
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    A Y-chromosome shredding gene drive for controlling pest vertebrate populations
    Prowse, TAA ; Adikusuma, F ; Cassey, P ; Thomas, P ; Ross, JV (eLIFE SCIENCES PUBL LTD, 2019-02-15)
    Self-replicating gene drives that modify sex ratios or infer a fitness cost could be used to control populations of invasive alien species. The targeted deletion of Y sex chromosomes using CRISPR technology offers a new approach for sex bias that could be incorporated within gene-drive designs. We introduce a novel gene-drive strategy termed Y-CHromosome deletion using Orthogonal Programmable Endonucleases (Y-CHOPE), incorporating a programmable endonuclease that 'shreds' the Y chromosome, thereby converting XY males into fertile XO females. Firstly, we demonstrate that the CRISPR/Cas12a system can eliminate the Y chromosome in embryonic stem cells with high efficiency (c. 90%). Next, using stochastic, individual-based models of a pest mouse population, we show that a Y-shredding drive that progressively depletes the pool of XY males could effect population eradication through mate limitation. Our molecular and modeling data suggest that a Y-CHOPE gene drive could be a viable tool for vertebrate pest control.